BIOINFORMATICS: April 2009

Clinical Trials
Clinical trials: Trials to evaluate the effectiveness and safety of medications or medical devices by monitoring their effects on large groups of people.
Clinical research trials may be conducted by government health agencies such as NIH, researchers affiliated with a hospital or university medical program, independent researchers, or private industry.
Depending on the type of product and the stage of its development, investigators enroll healthy volunteers and/or patients into small pilot studies initially, followed by larger scale studies in patients that often compare the new product with the currently prescribed treatment. As positive safety and efficacy data are gathered, the number of patients is typically increased. Clinical trials can vary in size from a single center in one country to multicenter trials in multiple countries.
Usually volunteers are recruited, although in some cases research subjects may be paid. Subjects are generally divided into two or more groups, including a control group that does not receive the experimental treatment, receives a placebo (inactive substance) instead, or receives a tried-and-true therapy for comparison purposes.
Typically, government agencies approve or disapprove new treatments based on clinical trial results. While important and highly effective in preventing obviously harmful treatments from coming to market, clinical research trials are not always perfect in discovering all side effects, particularly effects associated with long-term use and interactions between experimental drugs and other medications.
For some patients, clinical research trials represent an avenue for receiving promising new therapies that would not otherwise be available. Patients with difficult to treat or currently "incurable" diseases, such as AIDS or certain types of cancer, may want to pursue participation in clinical research trials if standard therapies are not effective. Clinical research trials are sometimes lifesaving.
There are four possible outcomes from a clinical trial:
Positive trial -- The clinical trial shows that the new treatment has a large beneficial effect and is superior to standard treatment.
Non-inferior trial -- The clinical trial shows that that the new treatment is equivalent to standard treatment. Also called a non-inferiority trial.
Inconclusive trial -- The clinical trial shows that the new treatment is neither clearly superior nor clearly inferior to standard treatment.
Negative trial -- The clinical trial shows that a new treatment is inferior to standard treatment.

History
Clinical trials were first introduced in Avicenna's The Canon of Medicine in 1025 AD, in which he laid down rules for the experimental use and testing of drugs and wrote a precise guide for practical experimentation in the process of discovering and proving the effectiveness of medical drugs and substances. He laid out the following rules and principles for testing the effectiveness of new drugs and medications, which still form the basis of modern clinical trials:

1."The drug must be free from any extraneous accidental quality."
2."It must be used on a simple, not a composite, disease."
3."The drug must be tested with two contrary types of diseases, because sometimes a drug cures one disease by its essential qualities and another by its accidental ones."
4."The quality of the drug must correspond to the strength of the disease. For example, there are some drugs whose heat is less than the coldness of certain diseases, so that they would have no effect on them."
5."The time of action must be observed, so that essence and accident are not confused."
6."The effect of the drug must be seen to occur constantly or in many cases, for if this did not happen, it was an accidental effect."
7."The experimentation must be done with the human body, for testing a drug on a lion or a horse might not prove anything about its effect on man."
One of the most famous clinical trials was James Lind's demonstration in 1747 that citrus fruits cure scurvy. He compared the effects of various different acidic substances, ranging from vinegar to cider, on groups of afflicted sailors, and found that the group who were given oranges and lemons had largely recovered from scurvy after 6 days.

Possible advantages
Clinical trials are done with the sole aim of testing medicines, medical devices and treatments that will ultimately be made available for human health. By participating in trials:
You may gain access during and after the clinical trial to new treatments that are not yet available to the general population
You may obtain medical care free of charge
You will be closely monitored for possible adverse events
You are contributing to medical research that may result in the advancement of medicine and healthcare in general thereby helping other fellow human beings
Participating in clinical trials is not a source of primary or additional income. However almost all sponsors reimburse persons that participate in trials for all reasonable expenses related to participating in the trial, including travel expenses, food, medical care and compensation for provable and insured adverse events that are related to the trial.

Possible disadvantages
There may be serious adverse events (SAEs) that are related to the medications used or procedures that are done in the trial; however study participants are intensively monitored so that SAEs may be detected early and managed appropriately. There is also insurance cover for some SAEs, so that participants may be compensated accordingly.
The medicines, vaccines, medical devices or treatment options used in the trial may not be effective for your disease; there are, however, safety procedures in place so that those participants who do not benefit from the trial medical management options may be switched to alternative effective treatment immediately or at the end of the trial.
The trial guidelines may require some adjustment of one or more aspects of your life, such as:
You may need to set aside time for trial related activities like visiting the trial site
You may not use certain medications including traditional medications without the approval of your trial doctor
Your personal private or social life may be affected, e.g. sexual activity, reproductive functioning, consumption of alcohol, tobacco or other drugs of abuse, etc.
You may have to consult your usual healthcare provider for all your other illnesses that are not related to the trial, but still you have to inform your provider that you are part of a trial and that certain medications or treatment options may not be compatible with your trial protocol
Your employer, medical aid, personal insurance and/or Commissioner for Compensation for Occupational Injuries may not pay for claims that are related to events due to your participation in clinical trials; it is therefore extremely important that you verify that the sponsor of the trial has an appropriate comprehensive insurance cover for you.

Design Of Clinical Trials
A fundamental distinction in evidence-based medicine is between observational studies and randomized controlled trials. Types of observational studies in epidemiology such as the cohort study and the case-control study provide less compelling evidence than the randomized controlled trial. In observational studies, the investigators only observe associations (correlations) between the treatments experienced by participants and their health status or diseases.
A randomized controlled trial is the study design that can provide the most compelling evidence that the study treatment causes the expected effect on human health.
Currently, some Phase II and most Phase III drug trials are designed as randomized, double blind, and placebo-controlled.
Randomized: Each study subject is randomly assigned to receive either the study treatment or a placebo.
Blind: The subjects involved in the study do not know which study treatment they receive. If the study is double-blind, the researchers also do not know which treatment is being given to any given subject. This 'blinding' is to prevent biases, since if a physician knew which patient was getting the study treatment and which patient was getting the placebo, he/she might be tempted to give the (presumably helpful) study drug to a patient who could more easily benefit from it. In addition, a physician might give extra care to only the patients who receive the placebos to compensate for their ineffectiveness. A form of double-blind study called a "double-dummy" design allows additional insurance against bias or placebo effect. In this kind of study, all patients are given both placebo and active doses in alternating periods of time during the study.
Placebo-controlled: The use of a placebo (fake treatment) allows the researchers to isolate the effect of the study treatment.
Although the term "clinical trials" is most commonly associated with the large, randomized studies typical of Phase III, many clinical trials are small. They may be "sponsored" by single physicians or a small group of physicians, and are designed to test simple questions. In the field of rare diseases sometimes the number of patients might be the limiting factor for a clinical trial. Other clinical trials require large numbers of participants (who may be followed over long periods of time), and the trial sponsor is a private company, a government health agency, or an academic research body such as a university.

Clinical Trial Design — What do probability and statistics have to do with it?
People are familiar with the idea of random variability. When you flip a coin 10 times, you “expect” 5 heads and 5 tails—but you’re not at all surprised to get different numbers. Perhaps this time you might get 6 and 4 . . . or perhaps 4 and 6. You could get 7 and 3, and you wouldn’t be knocked out of your chair if you got 8 and 2.
In fact, the chance of a theoretically “perfect” 5 and 5 outcome is only 24.6%. In other words, if 100 people try flipping a coin 10 times, only about 25 of them would see the “correct” ratio.
The chance discussed above—of getting 8 heads—has 4.4% probability. Since the chance of 8 tails is the same, their combined probability is 4.4% + 4.4% = 8.8%. So, out of 100 people, we’d expect about 9 to get either 8 heads and 2 tails or else 2 tails and 8 heads. In practice, lopsided outcomes are a definite, if infrequent, occurrence: some observers will get them. The probability of all heads is only 0.1% so, in a hundred people, we likely wouldn’t see anybody getting that; but in a crowd of 1000 people there could be 1 with all heads—and another with all tails.
In clinical trials the variation arises because the random selection of subjects and their random assignment to treatment could bring an atypically large number of “difficult” or of “easy” subjects to one treatment over the other. Treatment A, which has a true success rate of 50%, could easily show 3 successes in 10 subjects, while Treatment B, which has a true rate of only 40%, could show 5 successes in 10 subjects. Then, based on our total combined sample of 20, we could become wrongly, stubbornly convinced that Treatment B is better.
The squares in the gray-shaded diagonal represent outcomes in which an equal number of successes are observed for both treatments, even though Treatment A is superior. The sum total of the probabilities of these outcomes equals 16.0%. In practical terms, if this were an experiment assigned by a biology professor to a class of 100 students, it could be expected that 16 students would get data wrongly suggesting that the two treatments are equally effective. The black-shaded squares above the diagonal represent outcomes in which Treatment B is observed to have more successes than Treatment A. The combined probability of these outcomes equals 24.8%, so the biology professor can expect about 25 of the 100 students to submit lab reports concluding wrongly that Treatment B is superior. Only 59 students in the class of 100 will observe data (the white shaded squares below the diagonal) that will lead them to the correct conclusion.

Clinical trial protocol
A clinical trial protocol is a document used to gain confirmation of the trial design by a panel of experts and adherence by all study investigators, even if conducted in various countries.
The protocol describes the scientific rationale, objective(s), design, methodology, statistical considerations, and organization of the planned trial. Details of the trial are also provided in other documents referenced in the protocol such as an Investigator's Brochure.
The protocol contains a precise study plan for executing the clinical trial, not only to assure safety and health of the trial subjects, but also to provide an exact template for trial conduct by investigators at multiple locations (in a "multicenter" trial) to perform the study in exactly the same way. This harmonization allows data to be combined collectively as though all investigators (referred to as "sites") were working closely together. The protocol also gives the study administrators (often a contract research organization) as well as the site team of physicians, nurses and clinic administrators a common reference document for site responsibilities during the trial.
The format and content of clinical trial protocols sponsored by pharmaceutical, biotechnology or medical device companies in the United States, European Union, or Japan has been standardized to follow Good Clinical Practice guidance[10] issued by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).[11] Regulatory authorities in Canada and Australia also follow ICH guidelines. Some journals, e.g. Trials, encourage trialists to publish their protocols in the journal.

Design features

Informed consent
An essential component of initiating a clinical trial is to recruit study subjects following procedures using a signed document called "informed consent."[12]
Informed consent is a legally-defined process of a person being told about key facts involved in a clinical trial before deciding whether or not to participate. To fully describe participation to a candidate subject, the doctors and nurses involved in the trial explain the details of the study. Foreign language translation is provided if the participant's native language is not the same as the study protocol.
The research team provides an informed consent document that includes trial details, such as its purpose, duration, required procedures, risks, potential benefits and key contacts. The participant then decides whether or not to sign the document in agreement. Informed consent is not an immutable contract, as the participant can withdraw at any time.

Statistical power
In designing a clinical trial, a sponsor must decide on the target number of patients who will participate. The sponsor's goal usually is to obtain a statistically significant result showing a significant difference in outcome (e.g., number of deaths after 28 days in the study) between the groups of patients who receive the study treatments. The number of patients required to give a statistically significant result depends on the question the trial wants to answer. For example, to show the effectiveness of a new drug in a non-curable disease as metastatic kidney cancer requires many fewer patients than in a highly curable disease as seminoma if the drug is compared to a placebo.
The number of patients enrolled in a study has a large bearing on the ability of the study to reliably detect the size of the effect of the study intervention. This is described as the "power" of the trial. The larger the sample size or number of participants in the trial, the greater the statistical power.
However, in designing a clinical trial, this consideration must be balanced with the fact that more patients make for a more expensive trial. The power of a trial is not a single, unique value; it estimates the ability of a trial to detect a difference of a particular size (or larger) between the treated (tested drug/device) and control (placebo or standard treatment) groups. By example, a trial of a lipid-lowering drug versus placebo with 100 patients in each group might have a power of .90 to detect a difference between patients receiving study drug and patients receiving placebo of 10 mg/dL or more, but only have a power of .70 to detect a difference of 5 mg/dL.

Placebo groups
Merely giving a treatment can have nonspecific effects, and these are controlled for by the inclusion of a placebo group. Subjects in the treatment and placebo groups are assigned randomly and blinded as to which group they belong. Since researchers can behave differently to subjects given treatments or placebos, trials are also doubled-blinded so that the researchers do not know to which group a subject is assigned.
Assigning a person to a placebo group can pose an ethical problem if it violates his or her right to receive the best available treatment. The Declaration of Helsinki provides guidelines on this issue.

Phases of a Clinical Trial

Phase 0
Phase 0 is a recent designation for exploratory, first-in-human trials conducted in accordance with the U.S. Food and Drug Administration’s (FDA) 2006 Guidance on Exploratory Investigational New Drug (IND) Studies.Phase 0 trials are also known as human microdosing studies and are designed to speed up the development of promising drugs or imaging agents by establishing very early on whether the drug or agent behaves in human subjects as was expected from preclinical studies. Distinctive features of Phase 0 trials include the administration of single subtherapeutic doses of the study drug to a small number of subjects (10 to 15) to gather preliminary data on the agent's pharmacokinetics (how the body processes the drug) and pharmacodynamics (how the drug works in the body).
A Phase 0 study gives no data on safety or efficacy, being by definition a dose too low to cause any therapeutic effect. Drug development companies carry out Phase 0 studies to rank drug candidates in order to decide which has the best pharmacokinetic parameters in humans to take forward into further development. They enable go/no-go decisions to be based on relevant human models instead of relying on sometimes inconsistent animal data.

Phase 1
In Phase I a small number of healthy volunteers are exposed to the research treatment. The method of delivery as well as the dosing regimen is explored during this phase, and side effects are noted. Before Phase I studies begin, experiments comparing the new treatment with the drug of choice for the planned condition have been done in laboratory models and in animal studies, as well as extensive animal toxicity studies.
There are different kinds of Phase I trials:
SAD
Single Ascending Dose studies are those in which small groups of subjects are given a single dose of the drug while they are observed and tested for a period of time. If they do not exhibit any adverse side effects, and the pharmacokinetic data is roughly in line with predicted safe values, the dose is escalated, and a new group of subjects is then given a higher dose. This is continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up (at which point the drug is said to have reached the Maximum tolerated dose (MTD).
MAD
Multiple Ascending Dose studies are conducted to better understand the pharmacokinetics & pharmacodynamics of multiple doses of the drug. In these studies, a group of patients receives multiple low doses of the drug, whilst samples (of blood, and other fluids) are collected at various time points and analyzed to understand how the drug is processed within the body. The dose is subsequently escalated for further groups, up to a predetermined level.
Food effect
A short trial designed to investigate any differences in absorption of the drug by the body, caused by eating before the drug is given. These studies are usually run as a crossover study, with volunteers being given two identical doses of the drug on different occasions; one while fasted, and one after being fed.

Phase II
In Phase II, the effectiveness of the new treatment is characterized. The new drug is examined in patients using strict design criteria - appropriate monitoring, use of adequate controls, careful exploration of the effective and safe dose range, etc. Phase II studies are sometimes divided into Phase IIA and Phase IIB.
Phase IIA is specifically designed to assess dosing requirements (how much drug should be given).
Phase IIB is specifically designed to study efficacy (how well the drug works at the prescribed dose(s)).
Some trials combine Phase I and Phase II, and test both efficacy and toxicity.
Some Phase II trials are designed as case series, demonstrating a drug's safety and activity in a selected group of patients. Other Phase II trials are designed as randomized clinical trials, where some patients receive the drug/device and others receive placebo/standard treatment. Randomized Phase II trials have far fewer patients than randomized Phase III trials.

Phase III
In Phase III, large studies are done to compare the new medicament against a recognized standard treatment. Again, the studies must be well-controlled and well-conducted, to provide clear cut evidence of safety and effectiveness for the new drug regulatory authorities (e.g. FDA).
While not required in all cases, it is typically expected that there be at least two successful Phase III trials, demonstrating a drug's safety and efficacy, in order to obtain approval from the appropriate regulatory agencies such as FDA (USA), TGA (Australia), EMEA (European Union), or CDSCO/ICMR (India), for example.
Once a drug has proved satisfactory after Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life. This collection of information makes up the "regulatory submission" that is provided for review to the appropriate regulatory authorities[1] in different countries. They will review the submission, and, it is hoped, give the sponsor approval to market the drug.

Phase IV
Phase IV trial is also known as Post Marketing Surveillance Trial. Phase IV trials involve the safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives permission to be sold. Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive (finding a new market for the drug) or other reasons (for example, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials). The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials. Harmful effects discovered by Phase IV trials may result in a drug being no longer sold, or restricted to certain uses: recent examples involve cerivastatin (brand names Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx).

Ethical Conduct
Clinical trials are closely supervised by appropriate regulatory authorities. All studies that involve a medical or therapeutic intervention on patients must be approved by a supervising ethics committee before permission is granted to run the trial. The local ethics committee has discretion on how it will supervise noninterventional studies (observational studies or those using already collected data). In the U.S., this body is called the Institutional Review Board (IRB). Most IRBs are located at the local investigator's hospital or institution, but some sponsors allow the use of a central (independent/for profit) IRB for investigators who work at smaller institutions.
To be ethical, researchers must obtain the full and informed consent of participating human subjects. (One of the IRB's main functions is ensuring that potential patients are adequately informed about the clinical trial.) If the patient is unable to consent for him/herself, researchers can seek consent from the patient's legally authorized representative. In California, the state has prioritized the individuals who can serve as the legally authorized representative.
In some U.S. locations, the local IRB must certify researchers and their staff before they can conduct clinical trials. They must understand the federal patient privacy (HIPAA) law and good clinical practice. International Conference of Harmonisation Guidelines for Good Clinical Practice (ICH GCP) is a set of standards used internationally for the conduct of clinical trials. The guidelines aim to ensure that the "rights, safety and well being of trial subjects are protected".
The notion of informed consent of participating human subjects exists in many countries all over the world, but its precise definition may still vary.
Informed consent is clearly a necessary condition for ethical conduct but does not ensure ethical conduct. The final objective is to serve the community of patients or future patients in a best-possible and most responsible way. However, it may be hard to turn this objective into a well-defined quantified objective function. In some cases this can be done, however, as for instance for questions of when to stop sequential treatments (see Odds algorithm), and then quantified methods may play an important role.

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